What is the causality assessment for a case of liver cancer patient who developed upper gastrointestinal (GI) bleed 10 days after starting Lenvima (lenvatinib)?

From the Guidelines

There is a possible causal relationship between Lenvima (lenvatinib) and the upper gastrointestinal bleeding in this liver cancer patient, as supported by the known adverse effect profile of this medication 1. The temporal relationship is significant, with bleeding occurring 10 days after starting Lenvima, which is consistent with the known adverse effects of this medication. Lenvima is a multikinase inhibitor that targets vascular endothelial growth factor receptors (VEGFRs) and other pathways, which can impair vascular integrity and wound healing, increasing bleeding risk. In liver cancer patients, this risk may be further elevated due to potential portal hypertension, varices, or coagulopathy from underlying liver dysfunction.

Some key points to consider in this case include:

• The risk of gastrointestinal bleeding is a known adverse effect of multikinase inhibitors like lenvatinib, as noted in the guidelines for the management of hepatocellular carcinoma 1.
• The patient's liver function and potential presence of portal hypertension or varices should be carefully assessed, as these factors can increase the risk of bleeding.
• Alternative causes of bleeding should still be considered, including tumor-related bleeding, portal hypertension from cirrhosis, peptic ulcer disease, or other concurrent medications.

Management Considerations

Management should include:

• Immediate discontinuation of Lenvima to prevent further bleeding risk.
• Appropriate endoscopic evaluation and treatment of the bleeding source.
• Careful risk-benefit assessment before considering reintroduction of the medication, possibly at a reduced dose.
• Close monitoring for recurrent bleeding would be essential if treatment is resumed, as the risk of bleeding may persist.

It's also important to note that the British Society of Gastroenterology guidelines recommend careful assessment to identify potential contraindications to lenvatinib, including the risk of variceal bleeding, and that patients with portal hypertension should have had upper GI endoscopy within 6 months and adequately treated varices 1. The decision to restart Lenvima should be made on a case-by-case basis, taking into account the individual patient's risk factors and the potential benefits and risks of treatment 1.

From the FDA Drug Label

LENVIMA may cause serious bleeding problems that may lead to death. Tell your healthcare provider if you develop any signs or symptoms of bleeding during treatment with LENVIMA, including: severe and persistent nose bleeds vomiting blood red or black (looks like tar) stools blood in your urine coughing up blood or blood clots heavy or new onset vaginal bleeding

The patient developed upper GI bleed after 10 days of starting LENVIMA. Based on the drug label, bleeding is a possible side effect of LENVIMA. The temporal relationship between the start of LENVIMA and the development of upper GI bleed suggests a potential causal link. However, the label does not provide information on the incidence or risk factors for bleeding in patients with liver cancer.

• Causality assessment: Possible
• Key factors: Temporal relationship, known side effect of LENVIMA 2

From the Research

Causality Assessment for Upper GI Bleed in a Liver Cancer Patient After Starting Lenvima

• The patient developed upper GI bleed after 10 days of starting lenvatinib, which is an oral multikinase inhibitor used for the treatment of hepatocellular carcinoma (HCC) 3.
• Lenvatinib is associated with clinically important adverse events, including hypertension, diarrhea, decreased appetite/weight, hand-foot skin reaction, and proteinuria 3.
• However, upper GI bleed is not listed as a common adverse event associated with lenvatinib therapy in the expert consensus on the management of adverse events in patients receiving lenvatinib for HCC 3.
• A study on the incidence and predictors of esophagogastric varices bleeding in patients with HCC in lenvatinib found that the risk of EGV bleeding was mostly low but significant only in patients with high-risk EGV at baseline 4.
• Another study on lenvatinib-induced tumor-related hemorrhages in patients with large HCCs found that lenvatinib treatment can bring about tumor-related hemorrhages despite rapid suppression of tumor blood flow 5.
• The study suggests that lenvatinib quickly blocks the feeding circulation, resulting in tumor hemorrhage by necrosis, especially in patients with large HCCs 5.
• Therefore, it is possible that the upper GI bleed in this patient is related to the lenvatinib treatment, either due to the development of EGV bleeding or tumor-related hemorrhage 4, 5.
• However, further investigation is needed to determine the exact cause of the upper GI bleed and to assess the causality of the lenvatinib treatment 3, 4, 5.
• The management of adverse events, including upper GI bleed, plays an important role in continuing lenvatinib treatment, and clinicians should pay careful attention to the development of life-threatening hemorrhages when treating large HCCs with lenvatinib 3, 5, 6.